Orthopedics

Scientific Proceedings: Companion Animals Programme 1

Abstracts Voorjaarsdagen 2007 | 157
Reproduction
Premature Labor
Late term gestational loss attri-
buted to pre term or premature
labor is a controversial topic in
small animal reproduction. Both
hypoluteoidism and inappropriate
uterine activity accompanied by
cervical changes have been impli-
cated in the pathophysiology of
preterm birth in veterinary medicine, but the syndrome
is not well understood or even researched. While the
human literature is abundant on the topic, publications
on the topic are few in veterinary medicine.
Premature labor is defined here as uterine activity
and cervical changes leading to the loss of pregnancy
via resorption or abortion before term, for which no
metabolic, infectious, congenital, traumatic or toxic
cause is identified. Premature labor is associated with
progesterone levels that are <2 ng/ml. Premature labor is
often a retrospective diagnosis, achieved after thorough
evaluation of the dam and fetuses has been performed
because of loss of pregnancy. This evaluation should
include metabolic screening of the dam for systemic
disease, infectious disease evaluation, histopathology
of expelled fetuses and placentae, and review of kennel/
cattery husbandry including nutrition, medications and
environmental factors. All results are normal or negative.
Dams experiencing premature myometrial activity in one
pregnancy may or may not exhibit it during subsequent
pregnancies, but the syndrome can be a chronic cause of
failure to reproduce.
In human medicine, preterm birth complicates 10-12% of
human pregnancies, but it accounts for 80% of fetal mor-
bidity and mortality. The diagnosis of preterm labor plac-
ing the fetus at risk of premature delivery is dependent
upon evaluation of uterine contractility by tocodyna-
mometry, and fetal fibronectin and transvaginal cervical
length measurement determined via ultrasonography,
which together have high negative predictive value.
Amniocentesis is also advocated as a method of evalua-
ting fetal lung maturation and microbial invasion of the
amniotic cavity. The presence of contractions alone does
not warrant intervention. Tocodynamometry identifies
labor onset earlier than subjective maternal perceptions,
and home uterine monitoring is advocated in high risk
groups as an initial screening test. Multifetal gestations
(i.e. litters) are associated with exaggerated physiologic
changes which promote premature labor and compli-
Reproductive Disorders in the Dog and Bitch with Genetic Concerns
Autumn P. Davidson DVM, MS, DACVIM
Clinical Professor, School of Veterinary Medicine, University of California,
Davis, United States of America, apdavidson@ucdavis.edu
cate tocolytic therapy. Women with histories of preterm
deliveries do appear to be at risk for such in subsequent
pregnancies.
If intervention is indicated, tocolytics agents have been
commonly advocated. Antibiotics, bed and pelvic rest
and hydration do not appear to have benefit. Tocolytic
agents inhibit myometrial contractions, and include beta
mimetics (terbutaline, ritodrine), magnesium sulfate,
calcium channel blockers and prostaglandin synthetase
inhibitors (indomethacin, ketorolac, sulindac). Physicians
hope to intervene in the future with anticytokine
(interleukin-10) and antiprostaglandin therapy to more
completely suppress the pathogenic process at multiple
sites along the pathway rather than just treating the
processes at the end of preterm labor.
Small human trials based on prophylactic treatment
with progestational compounds have been reported.
Not all reported positive results with meta analysis,
the prevention of preterm delivery or the prevention
of recurrent miscarriage appears to be based on the
use of only the natural metabolite of progesterone, 17
alpha-hydroxyprogesterone caproate (17P). In one study,
no increase in the rate of congenital anomalies in the
progesterone group was noted over the control group.
The benefit of 17P in preventing preterm delivery appears
to be best in a cohort of women at very high risk, and the
cohort still exhibited a high rate of preterm delivery (36%)
despite significant reduction as compared to untreated
control (54%), indicating that other causes of preterm
delivery were at play. Tocolytic therapy was added in 17%
of the treated group and 16% of the untreated control
group. Interestingly, serum progesterone levels were not
reported.
The maintenance of canine and feline pregnancy
requires serum progesterone levels of >1-2 ng/ml.
Serum progesterone levels during pregnancy normally
range from 15 to 90 ng/ml, declining gradually during
the latter half of gestation, and falling abruptly at
term (usually the day before or the day of parturition).
Progesterone promotes the development of endometrial
glandular tissue, inhibits myometrial contractility
(causes relaxation of myometrial smooth muscle), blocks
the action of oxytocin, inhibits the formation of gap
junctions and inhibits leukocyte function in the uterus.
In several species, local changes in the progesterone level
or the ratio of progesterone to estrogen in the placenta,
decidua or fetal membranes is important in the initiation
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| Abstracts Voorjaarsdagen 2007 158
Reproduction Reproduction Reproduction
of labor. Progesterone antagonists administered at term
can result in an increased rate of spontaneous abortion.
In the bitch, the corpora lutea are the sole source of
progesterone, while in the queen, placental progesterone
production occurs in the latter half of gestation. Canine
luteal function is autonomous early in pregnancy but
supported by luteotrophic hormones (LH and prolactin)
after the second week of gestation.
Hypoluteiodism, primary luteal failure occurring before
term gestation, is a potential but not yet documented
cause of late term abortion in otherwise normal bitches.
It has been documented that the induction of abortion in
a normal but undesired pregnancy requires a reduction
of plasma progesterone levels <2 ng/ml. The diagnosis
of gestational loss caused by premature luteolysis is
difficult, requiring documentation of inadequate plasma
progesterone levels prior to abortion for which no other
cause is found. Measurement of precise progesterone
levels, especially in the critical 1-3 ng/ml range, is not
accurate using currently available rapid in house Elisa
kits, necessitating the use of commercial laboratories
in most practice situations. A few academic and human
private laboratories provide more rapid (< 8h) turnaround,
facilitating the diagnosis.
Progesterone levels diminish in response to fetal
death, thus documentation of a low progesterone level
after an abortion does not establish the diagnosis of
hypoluteiodism as the primary cause for reproductive
failure. Administration of progesterone to maintain
pregnancy in dams with primary fetal abnormalities,
placentitis, or intrauterine infection can cause continued
fetal growth with the possibility of dystocia and sepsis.
Administration of excessive progesterone to maintain
pregnancy in a dam not actually requiring therapy can
delay parturition and impact lactation, endangering the
life of the bitch and her fetuses, and can masculinize
female fetuses.
Dams with documented low progesterone levels and
historical late term loss of pregnancy with no apparent
pathology can also be also evaluated for premature myo-
metrial activity mid gestation, using uterine monitoring.
Elaboration of prostaglandins from the endometrium and
placenta associated with premature myometrial activity
can result secondarily in luteolysis. Premature uterine
activity endangering fetal survival can be identified before
significant luteolysis occurs, and intervention indicated
if the pregnancy is normal otherwise. Pharmacologic
intervention to decrease myometrial activity is indicated,
using progestational compounds and tocolytic agents
alone or in combination.
Therapeutic intervention in primary hypoluteoidism can
be accomplished with the administration of injectable
natural progesterone or oral synthetic progestagens.
Total serum levels of progesterone can be monitored
only when supplemented with the natural product.
Progesterone in oil is given intramuscularly at 2 mg/kg
q 72h. Altrenogest (Regumate, Hoechst-Roussel), a syn-
thetic progestagen manufactured for use in the mare,
is dosed orally at 0.088 mg/kg q 24h. Both forms of
supplementation must be discontinued in a timely fash-
ion so as not to interfere with normal parturition, within
24h of the due date with the oral synthetic product, and
within 72 h with the natural, injectable depot form.
This requires accurate identification of gestational
length via prior ovulation timing (parturition expected
to occur 64-66 days from the LH surge or initial rise in
progesterone, or 56-58 days from the first day of cyto-
logic diestrus). Less accurate identification of gestational
length can be made from breeding dates (58-72 days
from the first breeding), radiography, or ultrasound.
Terbutaline (Brethine, Ciba Geigy) .03 mg/kg PO q 8h has
been used to suppress uterine contractility in bitches
and queens with historical loss of otherwise normal
pregnancies preterm. The dose is ideally titrated to effect
using tocodynamometry. Therapy is discontinued 24h
before term.
Further work evaluating the pathophysiology of pre-
mature labor and preterm delivery in the bitch and
queen is needed, including evaluation of the ovary,
placenta, myometrium and fetus for contributing factors.
Multicenter studies including identification of the criteria
for diagnosis of significant premature labor, specific
therapy, outcome and follow up (dam and neonatal
health, subsequent pregnancies) is encouraged.
Inappropriate Maternal Behavior
Appropriate maternal behavior is critical to neonatal
survival and includes attentiveness, facilitation of nur-
sing, retrieving neonates, grooming and protecting
neonates. Although maternal behavior is instinctual,
it can be negatively influenced by anesthetic drugs,
pain, stress, and excessive human interference. Maternal
bonding is a pheromone mediated event initiated at
parturition. Whelping and queening should take place
in quiet, familial surroundings, with minimal human
interference, yet adequate supervision. Dams with good
maternal instincts exhibit caution when entering or
moving about the nest box so as not to traumatize
neonates by stepping or lying on them. A guardrail along
the inside of the whelping box prevents inadvertent
smothering of canine neonates.
The neuroendocrine reflex regulating mammary
gland myoepithelial cell contraction and subsequent
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milk ejection is mediated by oxytocin and activated by
neonatal suckling. During stress, epinephrine induces
vasoconstriction, blocking the entry of oxytocin into
the mammary gland and preventing milk ejection. A
nervous, agitated dam will likely have poor milk avail-
ability. Dopamine antagonist tranquilizers, with minimal
prolactin interference (ace promazine 0.01-0.02 mg/kg)
administered at the lowest effective dose to minimize
neonatal sedation, can improve maternal behavior and
mild ejection in nervous dams. Piling of littermates near
their dam facilitates the maintenance of their adequate
body temperature (neonates cannot thermoregulate/
shiver for up to 4 weeks of age) and makes nursing
readily available. Normal maternal behavior includes
gentle retrieval of neonates who have become dispersed
and isolated across the nest box. Grooming of the neo-
nates immediately following parturition stimulates their
cardiovascular and pulmonary function and removes
amniotic fluids. Dams demonstrating little interest in
resuscitating neonates can have poor maternal behav-
ior throughout the postnatal period. Later, maternal
grooming stimulates reflex neonatal urination and
defecation and maintains the neonatal coat in a clean,
dry state. Occasionally, excessive protective behavior or
fear-induced maternal aggression can occur. Mild tran-
quilization of the dam with an anti-anxiety agent can
help, but neonatal drug administration via the milk can
be problematic. Benzodiazepines, GABA synergists, are
reportedly superior to phenothiazines for fear-induced
aggression (diazepam 0.55-2.2 mg/kg). The role of newer
anti-anxiety pharmaceuticals in maternal aggression
has not been described in a controlled setting.
Hypothyroidism
Hypothyroidism is perceived by the dog fancy to be a
common disorder of great concern. Hypothyroidism is
blamed for sub-optimal hair coats, tendencies to gain
weight, reproductive problems and lackluster athletic
performances. Hypothyroidism is perceived by the
veterinary community as a frustrating disorder to cor-
rectly diagnose, or, more commonly not diagnose.
Many dogs presented to reproductive clinicians are
already on thyroid supplementation, generally sodium
levothyroxine, less commonly sodium liothyronine or a
combination product. Some of these dogs have historical
laboratory and clinical data supporting the diagnosis of
hypothyroidism, but many may not. Most commonly,
the diagnosis of hypothyroidism was made based on a
single total T4, usually part of a comprehensive general
chemistry profile, and often performed when the dog
was ill or on confounding medication. Some dogs have
been placed on thyroid supplementation by referring
veterinarians based on perceived clinical signs, without
clinical documentation of hypothyroidism. Some dogs
have had numerous thyroid tests performed, all with
normal results, but were then placed on supplementation
anyway as a therapeutic trial. Mention of breed specific
normals higher than established normal levels at
commercial laboratories has been made as a rationale
for therapy despite euthyroid test results. Some clients
have given their dogs thyroid supplementation at their
breeders insistence.
Most clients perceive thyroid supplementation as harmless
at worst, and are unaware of and unhappy to learn about
resultant iatrogenic hypothyroidism. Most are reluctant
to wean their dog off thyroid supplementation to permit
meaningful testing. Veterinarians are understandably
reluctant to discontinue thyroxine supplementation in
bitches presented for infertility, even if there was no
compelling evidence the individual was hypothyroid.
Evaluation of these dogs requires time and multiple tests
as the thyroid axis is re established. Dosages of sodium
levothyroxine are frequently lower than recommended
(22 ug/kg body weight q12h), but post pill tests are
normal. Annual re-evaluation of post pill thyroid levels is
usually uncommon.
Diagnostics: Any T4 result should be interpreted in light
of the dogs clinical signs, CBC and chemistry results
and additional thyroid testing if indicated. Currently,
diagnostic laboratories tend to utilize chemiluminescence
methodology for T4 testing, which has an excellent
correlation with radioimmunoassay, the gold standard.
Adequate and complete laboratory evaluation of the
thyroid status of the dog can be accomplished using 1 or
more of the following tests. The total T4 concentration,
if normal and over 2.0 ug/dl rules out hypothyroidism
in >95% of dogs. It is thought to be the best screening
test, except in the presence of antithyroid antibodies or
significant non-thyroidal illness. Antithyroid antibodies
artificially elevate T4 values in a radioimmunoassay.
Significant non-thyroidal illness can lower measured
T4 levels in euthyroid dogs (euthyroid sick). If T4 levels
are low or high, a free T4 by equilibrium dialysis (FT4ED)
is useful. The FT4ED has a diagnostic sensitivity of
98%, specificity of 93%, and accuracy of 95%. Adding
the endogenous canine TSH test (cTSH) can improve
specificity to 98%. Thyroglobulin autoantibodies (TGAA)
aid in the diagnosis of immune mediated thyroiditis.
Hypothyroidism in the dog is usually secondary to
immune mediated thyroiditis. Veterinarians have tended
to prescribe thyroid supplementation as a panacea for
reproductive failure where no other etiology is defined.
What is believed (on the internet and in non reviewed
publications)? Information concerning the effects
of hypothyroidism on canine reproduction is largely
anecdotal. Hypothyroidism has been popularly asso-
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ciated with several reproductive problems; in the male:
infertility, poor libido, testicular atrophy and azoospermia;
in the female: infertility, persistent anestrus, irregular
estrous cycles, abortion, galactorrhea and high neonatal
mortality. Hypothyroidism is not always accompanied by
reproductive disorders, normal pregnancy and whelping
has occurred in bitches with documented, untreated
hypothyroidism. No studies exist showing that fertility
in healthy, normal dogs has been enhanced by thyroxine
supplementation.
What is actually known (documented by peer reviewed
research and publications)? Thyroid hormones are
reported to support ovarian granulosa cell function
and placental trophoblast function. Thyroid hormones
have also been reported to support testicular growth,
gametogenesis, and Leydig cell development. Reports
of diminished libido, diminished spermatogenesis,
and abnormal sperm morphology and motility as a
consequence of hypothyroidism have been negated
by a controlled study. Libido, total sperm count, and
scrotal width have been shown not to be affected
by hypothyroidism induced by I 131. Hypothyroidism
can cause prolongation of the interestrous interval, a
reversible condition. In one study of 35 bitches diagnosed
as hypothyroid based on TRH stimulation testing or
thyroid scintigraphy, reproductive failure was reportedly
reversed with thyroxin supplementation.
Some details of reproductive implications of hypo-
thyroidism in human medicine are of interest. In
humans, subclinical hypothyroidism has been associated
with reduced fertility and a twice-normal rate of spon-
taneous abortion. Interestingly, the conception rate is
not reportedly affected, yet this is the concern of most
breeders. Women with multiple recurrent spontaneous
abortions are more commonly hypothyroid. Thyroid
antibodies are not thought to have an adverse effect
on pregnancy; rather, a general tendency toward the
development of autoimmunity exists. The most common
complication of autoimmune thyroiditis associated
with pregnancy in women is progressive postpartum
thyroiditis, resulting in overt hypothyroidism four or
more years later.
Hypothalamic anterior pituitary function has been
reported to be abnormal in hypothyroid children.
Although in most children thyroid hormone deficiency
leads to delayed sexual development, occasional children
manifest precocious sexual maturation. Increased
levels of circulating gonadotropins have been mea-
sured in both male and female children with such
manifestations. In females, serum prolactin levels also
tend to be increased, and galactorrhea may occur if
serum estrogen levels are high enough to permit breast
development and lactogenesis. The mechanism of the
precocious gonadotropin and prolactin hypersecretion
is not clear. Delayed sexual development due to abnor-
malities of hypothalamic-pituitary function secondary
to hypothyroidism are reportedly more common in adole-
scent children. Puberty often is delayed or incomplete.
Additionally, the menstrual cycle may be irregular and
nonovulatory for longer than normal.
Because hypothyroidism is considered to have genetic
implications, clinicians should be very secure in their
diagnosis with breeding animals.
Agalactia
Agalactia is diagnosed in a post partum otherwise
healthy bitch with inadequate lactation to meet neonatal
demand. Normal gestational length and husbandry is
typical.
A determination that adequate lactation is evident
should be performed prior to elective C section, this helps
confirm that the gestation is at term. If an emergency
section is required, regardless of the status of lactation,
intervention can be indicated (see below). Bitches with
inadequate lactation at term should be thoroughly
evaluated for metabolic or inflammatory disorders
(metritis, eclampsia, mastitis), as well as nutritional
and hydration status and treated appropriately. Occult
illness may require evaluation of the hemogram, serum
chemistries and vaginal discharge, as well as ultrasound
evaluation of the uterus. The normal presence of
colostrum (typically not copious) should not be confused
with agalactia. The level of neonatal contentment and
weight gain indicates adequate lactation.
Lactation results from proper integration of mammary
parenchymal and glandular development during gesta-
tion, and is under the control of pituitary and ovarian
hormones (prolactin and estrogen). Milk let down is
promoted by oxytocin release, a reflex triggered by
nursing, therefore neonates must spend adequate time
suckling. Disruption of the pituitary-ovarian-mammary
gland axis can result in idiopathic agalactia. Agalactia can
be associated with premature delivery of neonates, and
is suspected (by breeders) to be a potential complication
of ovariohysterectomy performed at the time of a C
section. Because estrogen promotes lactogenesis, the
adequacy of mammary development should be assessed
prior to removal of the ovaries at C section. Bitches with
adequate lactogenesis at term should not be negatively
impacted by ovariohysterectomy; estrogen production
by the post partum ovaries is probably negligible. A
genetic component may be present with this disorder
(Bull Mastiffs).
Lactation can be promoted in many cases if treated
promptly. The administration of mini dose oxytocin
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(0.5-2.0 units per dose), subcutaneously, every 2 hours
should be initiated. The nurslings should be removed
from the dam prior to each injection, and replaced 30
minutes later. The neonates should be supplemented
adequately to insure survival, but not excessively, such
that they will suckle vigorously. Gentle hand stripping of
the mammary glands should take place if suckling is not
vigorous. Concurrent administration of metoclopramide,
subcutaneously (0.1-0.2 mg/kg) every 6-8 hours promotes
prolactin release. The administration of ace promazine at
mild tranquilization dosages may also facilitate milk
let down. Therapy should continue until lactation is
adequate, usually 12-24 hours later. Failure to establish
lactation with consequential failure to provide colostrum
to neonates should be addressed by giving immune
serum to the neonates, 100 ml/kg; this can be given
orally if within the first 24-36 hours or subcutaneously
thereafter to establish normal serum immunoglobulin
levels.
Acquired Male Subfertility/Infertility
This syndrome occurs in an apparently healthy, young,
formerly fertile stud dog with normal libido begins to
produce small litters or frequently fails to cover bitches.
Ideally, the breeding behavior of the dog should be
witnessed, to rule out problems with husbandry. Failure
to achieve a normal copulatory lock, due to poor breeding
habits (most commonly a dog that attempts to turn
before complete engorgement of the bulbis has occurred)
can cause poor breeding success. If breeding behavior is
normal, a complete physical examination, CBC, serum
chemistries, Brucella screening, urinalysis with culture
(sample acquired by cystocentesis), semen evaluation
with appropriate consideration of microbiology, and
ultrasound evaluation of the reproductive organs should
be performed to rule out infectious, septic and metabolic
causes of acquired subfertility.
Assessment of the thyroid status alleviates client
concerns (Total T4, fT4ed, TGAA and cTSH). Semen
cytology typically finds oligospermia, asthenospermia
and sperm morphologic abnormalities. Epithelial
cells, lymphocytes and monocytes are increased in
the ejaculate. Sperm to sperm agglutination may be
evident. Multiple semen evaluations over a 90-120 day
period should be performed to be valid. Complete azoo-
spermia should prompt evaluation of semen alkaline
phosphatase levels (an epididymal marker) to assess
libido and rule out bilateral obstructive disorders (if
> 5000 a testicular sample was obtained). Testicular
biopsy can be performed to characterize adequacy and
completeness of spermatogenesis and the intact pre-
sence of spermatogenic apparatus. Culture of the biopsy
specimen can be helpful if semen and urethral cultures
have been difficult to interpret or not performed due to
expense. If neutering is elected, the complete testicles
should be submitted for histopathologic evaluation.
Generally, no infectious, endocrinologic or metabolic
cause for the acquired subfertility can be identified.
Testicular biopsy often identifies lymphoplasmacytic
inflammation if performed early in the course of
disease. The measurement of or assessment for
anti-sperm antibodies would be of interest but are
not readily commercially available. The cause of this
inflammation is unknown, prior traumatic or infectious
etiologies are generally not identified. Some break in
the blood testes barrier is suspected, which may be
present without trauma. Biopsy late in the course of the
disorder shows no evidence of inflammation, instead
diminished spermatogenesis and atrophy is evident.
A familial tendency is suspected in some breeds (Bull
Mastiff, Bernese Mountain Dog). Testicular biopsy has
been shown not to increase the incidence of anti sperm
antibodies.
The diagnosis of premature immune mediated testicular
degeneration warrants a poor prognosis for return
to normal fertility. Assisted reproductive techniques,
such as intrauterine insemination, optimal ovulation
timing, and semen banking can improve pregnancy
rates somewhat for a limited period of time. The use
of immunosuppressive agents is contraindicated due
to their effect on spermatogenesis. The heritability of
the disorder should be discussed with a client before
proceeding with heroics.
References available upon request.
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